This Phase I SBIR proposal is in response to Program Announcement PAR-98-073, "SBIR-AT-NIAID," which targets the development of new HIV-1 therapies using advanced technologies. A major goal of HIV-1 research is the development of noel agents that are broadly active against wild-type and multidrug resistant strains of HIV-1. HIV-1 reverse transcriptase (RT) remains an attractive target for development of a new generation of anti-retroviral agents with improved resistance, pharmacokinetic and safety profiles. The goal of this project is to exploit our recent findings on RT inhibition to discover novel NNRTIs with new modes of action and resistance profiles. The active form of HIV-1 RT is a p66-p51 heterodimer. Using the yeast two-hybrid system, we recently discovered that non-nucleoside RT inhibitors (NNRTIs) act by strongly promoting RT dimerization. This observation has led to the development of novel screening methods with the potential to identify chemically and/or mechanistically novel NNRTIs that may be overlooked in traditional screens for RT activity. Our specific goals are to adapt and validate our RT dimerization enhancement screen and perform high-throughput screening of combinatorial chemical libraries. Active compounds will be evaluated for breadth, potency and specificity of antiviral activity in order to select lead series of compounds for clinical development in the Phase II project. PROPOSED COMMERCIAL APPLICATIONS: This project seeks to develop chemically or mechanistically novel HIV-1 reverse transcriptase inhibitors. For an orally available drug that safely and effectively blocks HIV-1 replication and which acts in the same way as currently available NNRTIs, the market would be HIV-infected individuals who are suboptimally treated by existing therapies. These individuals include those with measurable viral loads despite highly active anti-retroviral therapy and those who experience significant treatment toxicities. Currently, these individuals comprise a sizeable, if not majority fraction of HIV-infected individuals, who currently number approximately 900,000 in the U.S. If the drug developed has a new mechanism of action, this would further expand the appropriate patient population.